Abstract
BackgroundMucopolysaccharidosis type I (MPS I) is a debilitating hereditary disease characterized by alpha-L-iduronidase (IDUA) deficiency and consequent inability to degrade glycosaminoglycans. The pathological accumulation of glycosaminoglycans systemically results in severe mental retardation and multiple organ dysfunction. Enzyme replacement therapy with recombinant human alpha-L-iduronidase (rhIDU) improves the function of some organs but not neurological deficits owing to its exclusion from the brain by the blood-brain barrier (BBB).MethodsWe divided MPS I mice into control group, enzyme replacement group with rhIDU 2.9 mg/kg injection, enzyme replacement with one-spot ultrasound treatment group, and enzyme replacement with two-spot ultrasound treatment group, and compare treatment effectiveness between groups. All ultrasound treatments were applied on left side brain. Evans blue was used to simulate the distribution of rhIDU in the brain.ResultsTranscranial pulsed weakly focused ultrasound combined with microbubbles facilitates brain rhIDU delivery in MPS I mice receiving systemic enzyme replacement therapy. With intravenously injected rhIDU 2.9 mg/kg, the IDUA enzyme activity on the ultrasound treated side of the cerebral hemisphere raised to 7.81-fold that on the untreated side and to 75.84% of its normal value. Evans blue simulation showed the distribution of the delivered drug was extensive, involving a large volume of the treated cerebral hemisphere. Two-spot ultrasound treatment scheme is more efficient for brain rhIDU delivery than one-spot ultrasound treatment scheme.ConclusionsTranscranial pulsed weakly focused ultrasound can open BBB extensively and facilitates brain rhIDU delivery. This novel technology may provide a new MPS I treatment strategy.
Highlights
Mucopolysaccharidosis type I (MPS I) is a debilitating hereditary disease characterized by alpha-Liduronidase (IDUA) deficiency and consequent inability to degrade glycosaminoglycans
Liver IDUA enzyme activity of MPS I mice was significantly higher in those injected with laronidase 2.9 mg/kg than those without treatment (Fig. 5), brain IDUA enzyme activity was similar between the groups (Fig. 6, group 1 and group 2), indicating that the blood-brain barrier (BBB) blocks the entry of laronidase to the brain
Mucopolysaccharidosis type I (MPS I), called Hurler syndrome, is an autosomal recessive disorder characterized by inability to degrade glycosaminoglycan (GAG) owing to a deficiency of alpha-L-iduronidase (IDUA)
Summary
Mucopolysaccharidosis type I (MPS I) is a debilitating hereditary disease characterized by alpha-Liduronidase (IDUA) deficiency and consequent inability to degrade glycosaminoglycans. With appropriate acoustic parameter settings, molecules as large as 2000 kDa can be successfully delivered to brain in the animal model [16] Most such studies have used pulsed strongly focused ultrasound to open BBB. The characteristic of pulsed strongly focused ultrasound is to concentrate acoustic energy to a small focal zone, BBB opening (BBBO) can be achieved in a small highly selective area within the brain [3,4,5,6,7,8, 10,11,12,13] This technique is appropriate for brain tumors, for which the therapeutic agents have to be delivered to a selective area. For diseases such as MPS I, where widespread delivery of therapeutic agents to the brain is needed, the use of pulsed unfocused ultrasound to open the BBB is more suitable [14, 15, 17,18,19]
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